Development of Chronic Inflammatory Arthropathy Resembling Rheumatoid Arthritis in Interleukin 1 Receptor Antagonist–Deficient Mice

TLDR

IL‑1 is a key pro‑inflammatory cytokine, and its endogenous inhibitor IL‑1ra normally restrains IL‑1 activity, yet the physiological functions of IL‑1ra remain largely unknown. The study seeks to determine the role of IL‑1ra by generating IL‑1ra‑deficient mice and examining their pathology across genetic backgrounds, with implications for rheumatoid arthritis. IL‑1ra knockout mice were produced via gene targeting, and their joint pathology was analyzed on BALB/cA and C57BL/6J backgrounds. BALB/cA IL‑1ra‑deficient mice spontaneously developed chronic inflammatory polyarthropathy resembling human rheumatoid arthritis, with synovial inflammation, articular erosion, autoantibody production, and overexpression of IL‑1β, IL‑6, and TNFα, demonstrating that IL‑1ra deficiency induces autoimmunity and joint inflammation and underscores its role in immune homeostasis.

Abstract

Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in inflammation, host defense, and the neuro-immuno-endocrine network. IL-1 receptor antagonist (ra) is an endogenous inhibitor of IL-1 and is supposed to regulate IL-1 activity. However, its pathophysiological roles in a body remain largely unknown. To elucidate the roles of IL-1ra, IL-1ra–deficient mice were produced by gene targeting, and pathology was analyzed on different genetic backgrounds. We found that all of the mice on a BALB/cA background, but not those on a C57BL/6J background, spontaneously developed chronic inflammatory polyarthropathy. Histopathology showed marked synovial and periarticular inflammation, with articular erosion caused by invasion of granulation tissues closely resembling that of rheumatoid arthritis in humans. Moreover, elevated levels of antibodies against immunoglobulins, type II collagen, and double-stranded DNA were detected in these mice, suggesting development of autoimmunity. Proinflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor α were overexpressed in the joints, indicating regulatory roles of IL-1ra in the cytokine network. We thus show that IL-1ra gene deficiency causes autoimmunity and joint-specific inflammation and suggest that IL-1ra is important in maintaining homeostasis of the immune system. Possible involvement of IL-1ra gene deficiency in RA will be discussed.